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Thrombophila and venous thromboembolismJan Kvasnika, Prague,CZ
Venous thrombosis is a multifactorial disease and analysis of the interactions between acquired and inherited risk factors is an extremely interesting field of investigation
A Silent Killer:VTE
VTE: Magnitude of the Problem in the United States1Hirsh J & Hoak J. Circulation 1996;93:2212-452Pengo V et al. N Engl J Med 2004;350:2257-643Brandjes DP et al. Lancet 1997;349:759-624Kahn SR et al. J Gen Intern Med 2000;26:425-960,0001600,0001800,0003,430,00022 million1VTE: Magnitude of the Problem in the United States
VTE According to Service (N=384)0255075100125150175OtherThoracic surgeryOrthopaedic surgeryMedical oncologyGeneral surgeryMedicalNumber of VTE eventsTotal VTEPEDVT4416109814Goldhaber SZ et al. Chest 2000;118:1680-4Total VTE (%) Patients
VTE: United StatesVTE accounts for >250,000 hospitalizations in the USA annually1,2PE has a 3-month mortality rate as high as 17%3VTE may lead to the debilitating post-phlebitic syndrome in as many as 33% of patients4
1Anderson F Jr et al. Arch Intern Med 1991;151:933-82Kim V et al. Emerg Med Clin North Am 2001;19:839-593Goldhaber SZ et al. Lancet 1999;353:1386-94Prandoni P et al. Ann Intern Med 1996;125:1-7
VTE: EuropeFrance: about 100,000 new cases of DVT are diagnosed each year and 20,000 fatal cases of PE per year2Germany: 180,000 new cases of DVT each year and 30,00040,000 fatal cases of PE per yearChronic thromboembolic pulmonary hypertension after PE: cumulative incidence 3.8% at 2 years (95% CI 1.1 to 6.5%)3UK: 90,000 cases of VTE each year of which 54,000 cases are PE1
1Datamonitor 20032Blanchemaison P. Phlbologie 1998;51:87-903Pengo V et al. N Engl J Med 2004;350:2257-64Partsch H et al. Phlebologie 2000;29:106
CI = confidence interval
Incidence of PE:Hospital vs General Population0910192029303940495059606970798089Age (years)Annual incidence of PE in a tertiary-care general hospital1 (% hospital admissions)PE is up to 10-fold higher in hospital population than in general population13
1Stein PD et al. Chest 1999;116:909-132Anderson F Jr et al. Arch Intern Med 1991;151:933-83Silverstein MD et al. Arch Intern Med 1998;158:585-93
acquired risk factors for VTEage, surgery,neoplasm,reduced mobility or paresis,among women - estrogen hormonal status (oral contraceptive, hormone replacement therapy, pregnancy ) is responsible for the majority of all venous thrombotic events,previous episode of deep vein thrombosis,controversial impact of other factors : obesity, tobacco use and varicose veins.
Oger E. et al. Ann Cardiol Angiol (Paris). 2002 Jun;51(3):124-8.
Annual incidence of venous thromboembolism among Olmsted County, Minnesota residents, 1966-90, by age and gender
Disease AssociationsEvidence-basedcardiac disease (acute MI/acute heart failure NYHA III/IV)infectious disease/sepsisactive cancer requiring therapyrespiratory diseases (respiratory failure with/without mechanical ventilation; exacerbation of chronic respiratory disease)rheumatic disease (including acute arthritis of lower extremities, vertebral compression, and acute back disorders)neurological disorders (stroke, paraplegia)Consensus-basedinflammatory disorders with immobilityinflammatory bowel disease
Primary diagnosis requiring admission or bedrest in patients >40 yearsCohen AT et al. J Thromb Haemost 2003;1 Suppl 1:OC437MI = myocardial infarctionNYHA = New York Heart Association
Exposing Risk Factors inMedical PatientsSamama MM et al. Haematologica 2003; 88:1410-21Odds RatioNYHA = New York Heart Association
Chronic obstructive pulmonary disease2.90Myocardial infarction3.33Acute cardiac heart failure,Stages NYHA III/IV3.00Pulmonary oedema3.41Ischaemic stroke without paralysis2.89Ischaemic stroke with paralysis5.00Malignant disease requiring treatment4.22Septicaemia, severe infections3.89
Risk Factors for VTE (1)Strong risk factors (odds ratio >10)fracture (hip or leg)hip or knee replacementmajor general surgerymajor traumaspinal cord injury
Anderson F & Spencer F. Circulation 2003;107:I09-I16
Risk Factors for VTE (2)Moderate risk factors (odds ratio 29)arthroscopic knee surgerycentral venous linechemotherapyCHF/respiratory failureHRT/oral contraceptive therapymalignancyprevious VTEparalytic strokepregnancy/post-partumthrombophilia
CHF = congestive heart failureHRT = hormone replacement therapyAnderson F & Spencer F. Circulation 2003;107:I09-I16
Risk Factors for VTE (3)Weak risk factors (odds ratio 3 dayssitting for prolonged periods, e.g. >8 hours of air travelincreased agelaparoscopic surgeryobesitypregnancy/antepartumvaricose veins
Anderson F & Spencer F. Circulation 2003;107:I09-I16
Individual Risk Assessmentfor Orthopaedic Surgery/Trauma
Score of exposing risk THR/TKR surgery Multiple trauma Spinal surgery in presence
of neurological disorders
Arthroscopy Plaster cast of lower limb Spinal surgery in absence
of neurological disorders
Operation 50 g)
Thrombophilic state History of VTE 1.5 Age >70 years
THR = total hip replacementTKR = total knee replacement Haas S. In: Memer K, Witte J, editors. Was gibt es Neues in der Chirurgie? Eco-med Verlag; Jahresband, 2002
Individual Risk Assessmentfor Internal Medicine Patients1023LowriskIncreasedriskLutz L, Haas S, Hach-Wunderle V, et al. Venous thromboembolism in internal medicine: risk evaluation and drug prophylaxis. Med Welt 2002;53:231-40123 Class of predisposing risk Dehydration Polycythaemia or
thrombocytosis Varicosis VTE in family HRT Obesity
Thrombophilia History of VTE Active malignancy
or 3 risks from
category 1 2 risks from
category 2 No basic risk
Age 65 years Pregnancy Oral contraception Nephrotic syndrome Myeloproliferative
syndrome 2 risks from
Ischaemic stroke with paralysis Acute decompensation of COPD with ventilation
MI Heart failure NYHA III + IV Acute decompensation of COPD without ventilation Sepsis Infection/acute inflammatory disease: bedrest
Infection/acute inflammatory disease: non-strict
bedrest Central venous lines or port system
No acute risk
0123COPD = chronic obstructive pulmonary diseaseHRT = hormone replacement therapy
Class of exposing risk
THROMBOPHILIA (synonymum hypercoagulable state)
- has been referred to as hereditary and / or acquired tendency to thrombosis. therefore the people with hereditary
thrombophilia are at constant, lifelong risk of thrombosis.
thrombusthrombophiliastimulusThrombogenesis A.I.Schafer (Lancet,1994,344:1739)VT is multifactorial disease, presence of different factors raises the risk : e.g. - relative risk of VT while thrombophilia FVL is approx. 2 -3x , but relative risk of VT while FVL and O.C. is 30x higher than in persons without these .
Genetic studiesMore than 40 genetic polymorphisms were described in over 25 hemostasis - related genes,
but only 2 of these polymorphisms have been consistently associated with thrombosis:mutation FV-Leiden 1691 GA,mutation FII 20210 GA.
Prevalence of Biologic Defects in Patients with Venous ThrombosisActivated Protein C Resistance (Factor V Leiden) 12 - 40%Prothrombin G20210A Mutation6 - 18%Deficiencies of Antithrombin III, PC, PS5 - 15%Hyperhomocysteinemia 10 - 20%Antiphospholid Antibody Syndrome 5 - 10%
Laboratory Evaluation of HypercoagulabilityScreening for resistance to activated protein C (APC) with clotting assay that dilutes patient plasma in factor V defficient plasma (confirm positive APC resistance assay genetically) or genetic test for Factor V Arg506Gln (Factor V Leiden)Genetic test for prothrombin G20210A mutationFunctional assay of antithrombin III (heparin-cofactor assay)Function assay of protein C Function assay of protein S along with immunological assays of total and free protein SClotting assay for lupus anticoagulant/ELISA for cardiolipin antibodies (IgG and IgM)Meassurment of fasting total plasma homocysteine levels
FV Leiden (Arg506Gln)
Real time PCR Light cycler (Roche)Crucial role in molecular medicine and clinical diagnostics, quick and reliable diagnostics.Performs rapid PCR in less than 30 min, simultaneously quantify and analyze the results by monitoring fluorescence during amplification.Detect mutations: changes in the melting curve analysis can be used to identify mutations.
MethodsWe included 496 carriers of FVL
(208 male and 287 female) who were treated at our Thrombotic Centre and ICEM Prague for VT, and age of the first VT episode was recorded. The FVL was tested by a conventional DNA amplification and restriction enzyme analysis / or by a real time PCR using Light cycler in the cohort of pts.
Ocurrence of first VT in male carriers of Factor V Leiden mutation
Ocurrence of first VT in female carriers of Factor V Leiden mutation.
Results The majority of the first VTs in FVL carriers registered for VTE in our centres were :at 20 - 29 years in female FVL carriers (26,5% from all; 68% used O.C.)